Method for treating or preventing the spread of acne vulgaris

ABSTRACT

Therapeutic treatment as well as prophylactic measures are provided by topical application of compositions containing an aryl 2-acetoxyethanoic acid to eradicate or prevent the development of axillary foul odor, foot malodor and other body odors, e.g. scalp, and skin, nail and follicular infections caused by microorganisms. The compositions are antimicrobial against several organisms that infect the skin and are specifically effective against P. acnes. The compositions are therapeutically effective against folliculitis and perifolliculitis and are useful for other skin lesions, nail and mucosal infections such as impetigo, seborrheic dermatitis, erythrasma and trichomycosis axillaris, associated with or caused by microorganisms. The therapeutic effect of the composition may be synergized or amplified by incorporating a cosmetic or dermatologic agent into the formulation for topical treatment of cosmetic and dermatologic indications. The compositions are also useful as preservatives in food products, cosmetic and pharmaceutical formulations, and industrial preparations.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 09/164,005, filed Sep. 30,1998, now U.S. Pat. No. 5,958,975, which is a division of applicationSer. No. 08/087,859, filed Feb. 26, 1997, now U.S. Pat. No. 5,807,890,which is a division of application Ser. No. 08/333,159, filed Nov. 1,1994, now U.S. Pat. No. 5,641,475, which is a continuation-in-part ofour application Ser. No. 08/276,275, filed Jul. 18, 1994, now U.S. Pat.No. 5,643,949 which is a division of application Ser. No. 08/132,837,filed Oct. 7, 1993, now abandoned, which is a division of applicationSer. No. 07/630,743, filed Dec. 20, 1990, now U.S. Pat. No. 5,258,391,which is a continuation of application Ser. No. 07/266,702, filed Nov.3, 1988, now abandoned, which is a continuation of application Ser. No.07/050,143, filed May 15, 1987, now abandoned.

FIELD OF THE INVENTION

The invention relates to antiodor, antimicrobial and preservativecompositions for prophylactic measures as well as topical treatment ofskin foul odor and infections caused by microorganisms. Moreparticularly, the invention is directed to compositions useful fortopical application to treat and to prevent the development of axillaryfoul odor, foot malodor and other body foul odor, and to alleviate skindisorders associated with microbial infections, and also useful aspreservatives in food products and cosmetic and pharmaceuticalformulations.

BACKGROUND OF THE INVENTION

In human skin, sebaceous glands, eccrine sweat glands and apocrineglands secrete various chemicals onto the skin surface. These chemicalsinclude sodium chloride, potassium bicarbonate, lactic acid, urea,squalene, proteins, carbohydrates, triglycerides and other lipids.Although body odor may be partially due to certain chemicals secreted bysebaceous glands and eccrine sweat glands, major axillary foul odor isdue to secretions of the apocrine glands, which contain special nutrientmaterials for microorganisms.

Apocrine glands are located primarily in the axillae, anogenital region,mammary areolae, ear canals, eyelids, and are scattered on parts of theface, anterior chest and abdomen. In general, the apocrine duct opensinto the upper end of the hair follicle although it may occasionallyopen directly onto the skin surface. In contrast to the eccrine glands,which produce a clear watery liquid, the apocrine glands secrete a milkyfluid that has a pH range of 5 to 6.5 and initially consists of lipids,proteins and carbohydrates. Although fresh apocrine secretions do nothave an objectionable odor, the secreted compounds are found to undergodecomposition by both chemical and microbial actions, and thedegradation products are responsible for the offensive odors. Chemicalsubstances identified as contributing to this unpleasant odor includelower organic acids such as butanoic, isopentanoic, hexanoic andoctanoic acids; mercaptans; indoles; amines; hydrogen sulfide; ammonia;and phosphine. Although gram-positive bacteria, thriving on substancesfound on the moist skin surface, appear to be responsible for theproduction of malodor, the precise mechanisms of odor production arestill unclear.

Most deodorant or antiperspirant products on the market today are saltsof aluminum or zinc. The aluminum salts include aluminum chloride,aluminum chlorhydroxide, aluminum sulfate, aluminum potassium sulfateand aluminum phenolsulfonate. The zinc salts comprise zinc oxide, zincperoxide, zinc stearate and zinc phenolsulfonate.

Although long-term use of aluminum or zinc salts as underarm deodorantspresents no major problems in toxicity, those compounds do frequentlycause irritation, burning, itching and other uncomfortable sensations tosome people with sensitive skin. These people stop using underarmdeodorants commonly available on the market today because of persistentitching or burning after use. Moreover, such irritation, burning anditching caused by underarm deodorants makes them even less suitable forapplication to other areas of the body which are even more sensitivethan the underarm. Development of other efficacious anti-odorantsubstances which do not cause irritation or uncomfortable sensation whenapplied to the skin is therefore desirable.

Nail infections may be caused by gram-positive bacteria such asStaphylococcus aureus and Streptococcus pyogenes; gram-negative bacteriasuch as Pseudomonas aeruginosa; dermatophytes such as Trichophytonrubrum and Trichophyton mentagrophytes; yeasts such as Candida albicansor herpes simplex virus. In general, nail infections are difficult totreat by topical application, because most commercially availableproducts are not formulated in bioavailable form to penetrate the hardnail plate.

Mucocutaneous integuments include for example oral mucosa, vaginalmucosa and anogenital areas. Although infections may be caused bybacteria, the most common forms are due to Candida yeasts and herpesvirus. Vulvar-vaginal infections may be caused for example byStaphylococcus aureus, Pseudomonas aeruginosa, Candida albicans,Trichomonas vaginalis, Gardnerella vaginalis, Corynebacteriumminutissimum or herpes simplex Type I or Type II virus. The yeastinfections are usually treated with butaconazole, clotrimazole,terconazole or miconazole cream for 3 to 7 days. The bacterialinfections may be treated with oral administration of metronidazole 500mg or clindamycin 300 mg twice daily for 7 days. For herpes infections,oral administration of acyclovir 200 mg 5 times daily for 10 days ortopical application of 5% acyclovir ointment may be prescribed withvarious degrees of effectiveness.

Folliculitis and perifolliculitis are inflammatory disorders within oraround the hair follicle, often caused by pathogenic bacteria or othermicroorganisms. The microorganisms may include Staphylococcus aureus,Pseudomonas aeruginosa, and Propionibacterium acnes. In most cases,scalp, face, chest, back and lower legs are involved. Folliculitis andperifolliculitis may be superficial infections and appear as smallpustules in or around hair follicles. However, deeper infections mayinclude lesions of papules and nodules. Patients may feel slightburning, itching and pain in the infected areas. Folliculitis may bepersistent and last for months and even years. Topical application ofmupirocin, chlorhexidine or aluminum chloride appears to be helpful andeffective in many instances.

In our U.S. Pat. No. 4,363,815, entitled "Alpha Hydroxyacids, AlphaKetoacids and Their Use in Treating Skin Conditions", we described andclaimed that certain alpha hydroxyacids and related compounds aretherapeutically effective for topical treatment of skin disordersassociated with disturbed keratinization or inflammation. Such skindisorders include dry skin, ichthyosis, palmar and plantarhyperkeratosis, dandruff, Darier's disease, lichen simplex chronicus,keratoses, acne, psoriasis, eczema, pruritus and possibly warts andherpes. The alpha hydroxyacids and related compounds disclosed in thepatent include phenyl 2-acetoxyethanoic acid (also known as phenyl alphaacetoxyacetic acid or O-acetylmandelic acid) which is a derivativecompound formed by acetylation of the hydroxy group of mandelic acid.

In our U.S. Pat. No. 5,258,391, entitled "Phenyl Alpha AcyloxyalkanoicAcids, Derivatives and Their Therapeutic Use", we disclosed and claimedcompositions containing these compounds for topical application topromote growth and hardening of nails and hair, wound healing andthickening of mucous membranes, skin and its appendages. However,compositions containing phenyl or diphenyl 2-acetoxyethanoic acid ortheir aryl or diaryl analogs have not previously been disclosed to beeffective and useful for topical application to alleviate skininfections and body foul odor caused by one or more microorganisms.

BRIEF SUMMARY OF THE INVENTION

According to the present invention, it has been found that aryl ordiaryl 2-acetoxyethanoic acids, when topically applied to body parts,such as the human axillae, foot or scalp, are useful in preventingand/or treating body foul odor. Further, according to the invention, ithas been found that the topical application of aryl or diaryl2-acetoxyethanoic acids to the skin, nails and mucosal membranes istherapeutically effective to eradicate or substantially improve skinlesions, such as folliculitis, perifolliculitis, impetigo, dandruff,seborrheic dermatitis, erythrasma and trichomycosis axillaris, and nailinfections and mucosal infections, including oral infections and vaginalinfections caused by various microorganisms. Further still, aryl ordiaryl 2-acetoxyethanoic acids are useful as preservatives in foodproducts, cosmetic and pharmaceutical formulations and industrialpreparations.

The aryl or diaryl 2-acetoxyethanoic acids may be applied in variousformulations such as solutions, gels, creams, lotions, stick, balm,sprays or powders in either anhydrous or aqueous vehicles. In addition,the compositions containing an aryl or diaryl 2-acetoxyethanoic acid maybe formulated or applied contemporaneously with other topical agents toprovide synergistic or amplified activity for cosmetic or dermatologicindications of the body part being treated.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In accordance with the present invention aryl or diaryl2-acetoxyethanoic acids which may be incorporated into topicalcompositions for body foul odor, skin, nail and mucosal infections andrelated dermatologic disorders or into food products, cosmetic orpharmaceutical formulations or industrial preparations as preservativestherefor, are shown by the following chemical structural formula##STR1## wherein R₁ =an aryl group having 6 to 13 carbon atoms, and R₂=H or an aryl group having 6 to 13 carbon atoms. The hydrogen atoms ofthe aryl groups may be substituted by an element or group such as F, Cl,Br, I, OH, AcO (acetoxy) or a saturated or unsaturated radical having 1to 9 carbon atoms, such as a lower alkyl or alkoxy.

Since R₁ and R₂ may both be aryl groups, the invention includes the useof both aryl and diaryl 2-acetoxyethanoic acids, but for ease ofreference the compounds of formula (I) will be simply referred to hereinas aryl 2-acetoxyethanoic acids. Aryl 2-acetoxyethanoic acids may alsoexist as stereoisomers such as D, L, and DL forms when R₁ and R₂ are notidentical. Aryl 2-acetoxyethanoic acids may also be present as a freeacid or a salt form with an inorganic or organic base.

Representative aryl 2-acetoxyethanoic acids include but are not limitedto the following: phenyl 2-acetoxyethanoic acid, (wherein in formula I:R₁ =C₆ H₅, R₂ =H); diphenyl 2-acetoxyethanoic acid, (wherein R₁ =C₆ H₅,R₂ =C₆ H₅); (4-methylphenyl) 2-acetoxyethanoic acid, (wherein R₁ =CH₃ C₆H₄, R₂ =H); (4-hydroxyphenyl) 2-acetoxyethanoic acid, (wherein R₁ =HOC₆H₄, R₂ =H); (4-chlorophenyl) 2-acetoxyethanoic acid, (wherein R₁ =ClC₆H₄, R₂ =H); (2-chlorophenyl) 2-acetoxyethanoic acid, (wherein R₁ =ClC₆H₄, R₂ =H); (4-acetoxyphenyl) 2-acetoxyethanoic acid, (wherein R₁ =CH₃COOC₆ H₄, R₂ =H); (4-chlorophenyl) (2-chlorophenyl) 2-acetoxyethanoicacid, (wherein R₁ =ClC₆ H₄, R₂ =ClC₆ H₄); (4-methylphenyl)(2-chlorophenyl) 2-acetoxyethanoic acid, (wherein R₁ =CH₃ C₆ H₄, R₂=ClC₆ H₄); and (2-Naphthyl) 2-acetoxyethanoic acid, (wherein R₁ =C₁₀ H₇,R₂ =H). Preferred aryl and diaryl 2-acetoxyethanoic acids include butare not limited to the following: phenyl 2-acetoxyethanoic acid;diphenyl 2-acetoxyethanoic acid; (4-chlorophenyl) 2-acetoxyethanoicacid; (2-chlorophenyl) 2-acetoxyethanoic acid; and (4-chlorophenyl)(2-chlorophenyl) 2-acetoxyethanoic acid.

Skin infections are generally caused by microbial agents which includebacteria, yeasts, fungi and viruses. It now appears that the aryl2-acetoxyethanoic acids may have cidal as well as static effects, i.e.,killing as well as inhibiting the growth of microorganisms. Thesecompounds can thus treat the infections as well as alleviating thesymptoms thereof.

We have now discovered that aryl 2-acetoxyethanoic acids haveunexpected, much broader therapeutic utility than previously described.Under standard microbial tests, this compound has been found to inhibitthe growth of various bacteria including Staphylococcus aureus,Staphylococcus epidermidis, Micrococcus sedentarius, Micrococcus luteus,Brevibacterium epidermis, Corynebacterium minutissium, Serratiamarcescens, Pseudomonas aeruginosa, Escherichia coli, andPropionibacterium acnes.

Aryl 2-acetoxyethanoic acid is specifically effective against the growthof P. acnes even in the presence of 10% lipid material in the testmedia. The inhibitory effect against P. acnes of this compound has beenfound to be greater than that of benzoyl peroxide under the same testconditions. Commonly used antiseptic compounds chlorhexidine gluconateand triclosan have been tested and compared under the same conditionsand were found to be effective against various bacteria in the absenceof lipid materials. However, chlorhexidine gluconate and triclosan havebeen found to be ineffective against most microorganisms when lipidmaterials are incorporated into the test media. In skin lesions, such asfolliculitis, lipid materials including sebum secreted by sebaceousglands are present. In contrast to these two compounds, aryl2-acetoxyethanoic acid has been found to be very effective against P.acnes even in the presence of lipid materials, particularly in treatingand preventing the spread of acne vulgaris.

We have now discovered that a composition containing aryl2-acetoxyethanoic acid is topically effective in preventing thedevelopment of, as well as in treating, body foul odor. Specifically,the composition is useful for topical application to prevent thedevelopment of axillary foul odor and foot malodor. The composition isalso therapeutically effective for topical treatment of underarm foulodor and foot malodor.

We have also discovered that the compositions are useful for topicalapplication to eradicate or substantially improve skin lesions such asfolliculitis, perifolliculitis, impetigo, dandruff seborrheicdermatitis, erythrasma and trichomycosis axillaris, and nail infectionsand mucosal infections including oral infections and vaginal infectionscaused by microbial organisms. These microorganisms includeStaphylococcus species such as S. aureus and S. epidermis; Coryneformspecies such as Brevibacterium; Propionibacterium acnes such as P.acnes, P. granulosum and P. avidum; gram-negative bacteria includingProteus and E. coli; gram-positive bacillus and mycobacteria; andPityrosporum species such as P. ovale, P. orbiculae and Malasseziafurfur.

Aryl 2-acetoxyethanoic acids may also be incorporated into a foodproduct or into a cosmetic or pharmaceutical composition as apreservative to prevent the growth of a microorganism.

We have further discovered that aryl 2-acetoxyethanoic acids can besynergistic to or can amplify the bioactivity of a dermatologic ortopical agent. For example, salicylic acid may be useful as akeratolytic agent for topical treatment of follicular lesions associatedwith comedones or follicular occlusions. Salicylic acid, however, is nottherapeutically effective against acne lesions associated withwhiteheads caused by microbial infections including P. acnes. Anamplifying composition containing salicylic acid and an effective amountof an aryl 2-acetoxyethanoic acid has been found to eradicate orsubstantially improve the clearing of both blackhead and whiteheadlesions caused by physiologic factors and microbial infections.

We have further discovered that aryl 2-acetoxyethanoic acids can reversea drug resistance to many dermatologic agents such as corticosteroids.For example, clobetasol propionate, betamethasone dipropionate,betamethasone valerate and triamcinolone acetonide are topicallyeffective in the improvement of psoriatic lesions. Many patients howeverdevelop drug resistance to continued medications, a phenomenon known astachyphylaxis or drug unresponsiveness. The cause for such drugunresponsiveness is unknown. It has been speculated that a receptormolecule for the corticosteroid might be depleted on chronic use oftopical corticosteroid. At the time when the tachyphylaxis occurred oncontinued use of a corticosteroid, a composition containing an aryl2-acetoxyethanoic acid was found to reverse such unresponsiveness, andpsoriatic lesions began to improve.

Dermatologic agents and topical agents of cosmetic or pharmaceuticalsubstances may be incorporated into the composition containing an aryl2-acetoxyethanoic acid to amplify the bioactivity for topical treatmentof various cosmetic and dermatologic indications. Topical agents whichmay he incorporated into the present composition include localanalgesics and anesthetics, antiacne agents, antibacterial agents,antiyeast agents, antifungal agents, antiviral agents, antidermatitisagents, antipruritic (antiitch) agents, antiinflammatory agents,antiperspirants, antipsoriatic agents, antiaging and antiwrinkle agents,sunscreen and sunblock agents, skin lightening agents, depigmentingagents, vitamins, corticosteroids, hormones and retinoids. Examples ofcosmetic and pharmaceutical agents include salicylic acid, pramoxine,clotrimazole, ketoconazole, miconazole, econazole, fluconazole,metronidazole, hydroxyzine, terbinafine, diphenhydramine, lidocaine,procaine, mepivacaine, monobenzone, erythromycin, tetracycline,clindamycin, meclocycline, hydroquinone, minocycline, naproxen,ibuprofen, theophylline, cromolyn, retinoic acid, 13-cis retinoic acid,hydrocortisone, hydrocortisone 21-acetate, hydrocortisone 17-valerate,hydrocortisone 17-butyrate, betamethasome valerate, betamethasonedipropionate, triamcinolone acetonide, fluocinonide, clobetasol,propionate, benzoyl peroxide, hydrogen peroxide, crotamiton,propranolol, promethazine, vitamin A palmitate, vitamin A acetate, andvitamin E acetate.

For example, treatment for nail infections may include compositionscontaining an aryl 2-acetoxyethanoic acid as the only active ingredientor compositions containing a dermatological or pharmaceutical agent anda synergistic amount of an aryl 2-acetoxyethanoic acid. Thedermatological and pharmaceutical agents include, for example,clotrimazole, miconazole, econazole, ketoconazole, metronidazole,griseofulvin, ciclopirox, nystatin, polymyxin, dicloxacillin,fluconazole and acyclovir.

Preparation Of Therapeutic/Prophylactic Compositions

Aryl 2-acetoxyethanoic acid compositions may be formulated in variousforms, such as a solution, gel, cream, stick, balm, lotion, spray orpowder form. In a typical anhydrous solution form, an aryl2-acetoxyethanoic acid is dissolved in a mixture of ethanol andpropylene glycol. The solution may contain the aryl 2-acetoxyethanoicacid in an amount from about 0.01% to about 99%, with a preferredconcentration of about 0.05% to about 10%; ethanol in an amount fromabout 1% to about 90%, with a preferred concentration of about 20% toabout 80%; and propylene glycol in an amount from about 1% to about 60%,with a preferred concentration of about 5% to about 40%. Unlessotherwise indicated, all liquid percentages stated herein areweight/volume percent.

In the preparation of a composition in powder form, the aryl2-acetoxyethanoic acid is first ground into fine powder with mortar andpestle or ball-mill machine, for example. The powdered substance is thenmixed thoroughly with talc powder. The concentration of aryl2-acetoxyethanoic acid may range from about 0.01% to about 20%, with apreferred concentration of about 0.02% to about 5%. Unless otherwiseindicated, all solid percentages stated herein are percent by weight oftotal composition.

To formulate a synergistic or amplified composition an aryl2-acetoxyethanoic acid may be directly incorporated into a compositioncontaining a topical agent for cosmetic or dermatologic indications.Aqueous formulations are also possible by dissolving the aryl2-acetoxyethanoic acid in ethanol, for example, then mixing with water.Propylene glycol and other common solvents may be added to suchalcoholic aqueous solutions. Alternatively, the topical agent may beapplied separately, but substantially contemporaneously, with the aryl2-acetoxyethanoic acid.

The invention will now be described in more detail with reference to thefollowing specific, non-limiting examples.

EXAMPLE 1

The following strains of microorganisms were used in Minimum InhibitoryConcentration (MIC) tests for phenyl 2-acetoxyethanoic acid in thisexample and for benzoyl peroxide, chlorhexidine gluconate and triclosanin the following examples. In total, five strains were used for S.aureus, five strains were used for S. epidermidis, two strains were usedfor M. sedentarius, three strains were used for M. luteus, two strainswere used for B. epidermis, three strains were used for C. minutissium,one strain was used for S. marcescens, three strains were used for P.aeruginosa, four strains were used for E. coli, and thirty-two strainswere used for P. acnes.

Antimicrobial effects were determined based on MIC Agar Dilution Testutilizing Trypticase Soy Agar II (BBL) incorporation plates with andwithout 10% intralipid (Kabi Pharmacia Inc.). Initially, phenyl2-acetoxyethanoic acid was prepared as a 2 mg/ml (0.2%) solution inwater. This solution with serial dilution was incorporated into the testagar plates. The MIC test gave similar results when the same species buta different strain was used.

    ______________________________________                                                                                                       MIC                               (μg/ml)                                                                    No Lipid                                                                             Lipid                                               ______________________________________                                        1.    Staphylococcus aureus                                                                            500      500                                           2.  Staphylococcus epidermidis      1000         1000                         3.   Micrococcus sedentarius          500          500                        4.   Micrococcus luteus              1000         1000                        5.   Brevibacterium epidermis        1000         1000                        6.   Corynebacterium minutissium      500          500                        7.  Serratia marcescens             1000         1000                         8.  Pseudomcnas aeruginosa          1000         1000                         9.  Escherichia coli                1000         1000                         10. Propionibacterium acnes          250          250                       ______________________________________                                    

The above results show that phenyl 2-acetoxyethanoic acid had inhibitoryeffects against all of the above bacteria, and the compound at 250 μg/ml(0.025%) concentration was specifically effective against the growth ofP. acnes even in the presence of 10% lipid materials.

EXAMPLE 2 (COMPARATIVE)

Under the same test conditions described in Example 1, benzoyl peroxidewas prepared as a 2.5 mg/ml (0.25%) solution in water. This solutionwith serial dilution was incorporated into the test agar plates. Typicaltest results are shown as follows.

    ______________________________________                                                                                                       MIC                               (μg/ml)                                                                    No Lipid                                                                             Lipid                                               ______________________________________                                        1.    Staphylococcus aureus                                                                            2500     1250                                          2.  Staphylococcus epidermidis       2500         1250                        3.  Micrococcus sedentarius          2500          650                        4.  Micrococcusluteus                2500          650                        5.  Brevibacterium epidermis         2500         1250                        6.  Corynebacterium minutissium      2500         1250                        7.  Serratia marcescens              72500        1250                        8.  Pseudomonas aeruginosa           72500        1250                        9.  Escherichia coli                 2500         1250                        10. Propionibacterium acnes          2500          625                      ______________________________________                                    

The above results show that benzoyl peroxide was moderately effectiveagainst the growth of the above bacteria excluding S. marcescens and P.aeruginosa when lipid materials were present in the test medium.

EXAMPLE 3 (COMPARATIVE)

Under the same test conditions described in Example 1, chlorhexidinegluconate was prepared as a 2 mg/ml (0.2%) solution in water. Thissolution with serial dilution was incorporated into the test agarplates. Typical test results are shown as follows.

    ______________________________________                                                                                                       MIC                               (μg/ml)                                                                    No Lipid                                                                             Lipid                                               ______________________________________                                        1.    Staphylococcus aureus                                                                            125      >2000                                         2.   Staphylococcus epidermidis       125          >2000                      3.   Micrococcus sedentarius          125          > 2000                     4.   Micrococcus luteus               125          > 2000                     5.   Brevibacterium epidermis         250         > 2000                      6.     Ccrynebacterium minutissium      125          > 2000                   7.   Serratia marcescens             1000          > 2000                     8.   Pseudcmcnas aerugincsa          1000         > 2000                      9.   Escherichia ccii                 250           >2000                     10.  Prcpicnibacterium acnes          62.5        >  2000                   ______________________________________                                    

The above results show that chlorhexidine gluconate was effectiveagainst the growth of the above bacteria when no lipid materials werepresent in the test medium. However, chlorhexidine gluconate was totallyineffective against the growth of the above bacteria when 10% lipidmaterials were incorporated in the test medium.

EXAMPLE 4 (COMPARATIVE)

Under the same test conditions described in Example 1, triclosan wasprepared as a 10 mg/ml (1%) solution in water. This solution with serialdilution was incorporated into the test agar plates. Typical testresults are shown as follows.

    ______________________________________                                                                                                       MIC                               (μg/ml)                                                                    No Lipid                                                                             Lipid                                               ______________________________________                                        1.    Staphylococcus aureus                                                                            156      >10000                                        2.   Staphylococcus epidermidis         156            5000                   3.   Micrococcus sedentarius            156          >10000                   4.   Microcqccus luteus                 156          >10000                   5.   Brevibacterium epidermis          156          >10000                    6.   Corynebacterium minutissium        156          >10000                   7.   Serratia marcescens           >   10000        > 10000                   8.   Pseudomonas aeruginosa          >10000     >    10000                    9.   Escherichia coli                   156           >10000                  10.  Propionibacterium acnes            156          >10000                 ______________________________________                                    

The above results show that triclosan was effective against the growthof the above bacteria excluding S. marcescens and P. aeruginosa in theabsence of lipid materials. However, triclosan was ineffective againstthe growth of the above bacteria when 10% lipid materials wereincorporated in the test medium.

EXAMPLE 5

A typical test for prophylactic effect in preventing the development ofaxillary foul odor was carried out as follows. A test composition wasprepared by dissolving 0.5 g of phenyl 2-acetoxyethanoic acid ordiphenyl 2-acetoxyethanoic acid in 70 ml of ethanol and 30 ml ofpropylene glycol. The control vehicle was prepared by mixing 70 ml ofethanol and 30 ml of propylene glycol. A human subject, male, age 71,was instructed to take a shower in the morning using ordinary soap toclean the body surfaces. After the skin was dried, the test compositionwas topically applied to the left underarm area only. The vehiclecontrol was topically applied to the right underarm area. Both underarmareas were monitored by the subject and at least one other personapproximately every 8 hours to determine whether the test compositionhad any prophylactic effect in preventing the development of underarmfoul odor in the left axilla as compared to the vehicle alone on theright control armpit.

Presence or substantial absence of foul odor, detected by smell, wasadopted as the criteria for ineffectiveness or effectiveness of the testcomposition. It was found that while the right control side developedfoul odor within hours, the left underarm did not produce any detectableodor, even after 24 hours. This shows that the test compositioncontaining 0.5% phenyl 2-acetoxyethanoic acid or diphenyl2-acetoxyethanoic acid was substantially effective in preventing thedevelopment of axillary foul odor.

EXAMPLE 6

A typical test for axillary antiodor effectiveness was carried out asfollows. A human subject, female, age 62, could not use existingcommercial products of antiperspirants or deodorants because of severeitching and irritation after topical application. After the foul odordeveloped in both axillae, the subject was instructed to apply the sametest composition as Example 5 containing 0.5% phenyl 2-acetoxyethanoicacid or diphenyl 2-acetoxyethanoic acid on the left side underarm andthe control vehicle on the right side. Topical applications were madeonce daily for several days.

While the right armpit continued to produce foul odor, the left underarmceased emanating any detectable foul odor after 1 day. The subject wasinstructed at this time to apply the test composition on the right sidealso. The right axilla ceased to emanate any detectable foul odor after1 day of use. This shows that the test composition containing phenyl2-acetoxyethanoic acid or diphenyl 2-acetoxyethanoic acid was topicallyeffective in eradicating the axillary foul odor.

EXAMPLE 7

A typical test for prophylactic effect in preventing the development of,as well as treatment of, foot malodor was carried out as follows. A testcomposition in powder form was prepared by mixing 1 g of finely powderedphenyl 2-acetoxyethanoic acid with 99 g of talc powder. The talc powderalone was used as a control vehicle.

A human subject, female, age 23, had persistent foot malodor all yearround. She had used commercially available foot products containing amixture of undecylenic acid and zinc or calcium undecylenate withpartial or little success in controlling the development of footmalodor. On the first morning, the subject was instructed to spread thetest composition lightly on the left foot and also inside the hose. Thecontrol vehicle was used on the right foot and inside the hose. Whilethe right foot developed malodor by the first evening, the left footproduced no detectable malodor. The subject was then instructed to applythe test composition on both feet the second morning. At the end of thesecond day, both feet produced no detectable malodor. The same topicalapplications were continued for several days; complete suppression ofmalodor was sustained. This shows that the test composition containingphenyl 2-acetoxyethanoic acid in powder form was topically effective inpreventing the development of and in treating foot malodor.

EXAMPLE 8

A prophylactic and therapeutic composition containing an aryl2-acetoxyethanoic acid and salicylic acid for topical treatment of skininfections may be formulated as follows. Phenyl 2-acetoxyethanoic acid1.0 g and salicylic acid 2.0 g were dissolved in a mixture consisting ofethanol 70 ml, propylene glycol 26 ml and nonoxynol-6 1.0 ml. Thesolution thus obtained had pH 2.9. The composition thus formulatedcontaining phenyl 2-acetoxyethanoic acid 1% and salicylic acid 2% issuitable for topical treatment of infected skin lesions includingpapular and pustular acne lesions.

EXAMPLE 9

A prophylactic and therapeutic composition containing an aryl2-acetoxyethanoic acid and chlorhexidine for topical treatment of skininfections and body odors may be formulated as follows. Phenyl2-acetoxyethanoic acid 0.3 g and chlorhexidine 0.1 g were dissolved in amixture consisting of ethanol 70 ml, propylene glycol 28.6 ml andnonoxynol-9 1.0 ml. The solution thus obtained had pH 4.6. Thecomposition thus formulated containing phenyl 2-acetoxyethanoic acid0.3% and chlorhexidine 0.1% is suitable for topical treatment of bodyodors as well as skin infections including papular and pustular acnelesions.

EXAMPLE 10

A prophylactic and therapeutic composition containing an aryl2-acetoxyethanoic acid and three other topical agents for topicaltreatment of skin infections may be formulated as follows. Phenyl2-acetoxyethanoic acid 0.9 g, salicylic acid 2.0 g, tartaric acid 0.9 gand citric acid 0.9 g were dissolved in a mixture consisting of ethanol70 ml, propylene glycol 24.4 ml and nonoxynol-11 0.9 ml. The solutionthus obtained had pH 2.1. The composition thus formulated containingphenyl 2-acetoxyethanoic acid 0.9%, salicylic acid 2%, tartaric acid0.9% and citric acid 0.9% is suitable for topical treatment of skininfections including, papular and pustular acne lesions.

EXAMPLE 11

A prophylactic and therapeutic composition containing an aryl2-acetoxyethanoic acid and other topical agents for topical treatment ofskin infections may be formulated as follows. Phenyl 2-acetoxyethanoicacid or diphenyl 2-acetoxyethanoic acid 0.9 g., salicylic acid 2.0 g,tartaric acid 0.9 g, citric acid 0.9 g, retinyl acetate 0.9 g, triethylcitrate 20 g and BHT 0.2 g were dissolved in a mixture consisting ofethanol 63.3 ml, propylene glycol 10 ml, and nonoxynol-11 0.9 ml. Thecomposition thus formulated containing aryl 2-acetoxyethanoic acid 0.9%,salicylic acid 2%, tartaric acid 0.9%, citric acid 0.9%, retinyl acetate0.9% and triethyl citrate 20% is suitable for topical treatment of skininfections including papular and pustular acne lesions.

EXAMPLE 12

A topical composition containing 3% aryl 2-acetoxyethanoic acid as theonly active ingredient for treatment of nail infections may beformulated as follows: phenyl 2-acetoxyethanoic acid or diphenyl2-acetoxyethanoic acid 3 g was dissolved in isopropyl alcohol 77 ml,butane-1,3-diol 15 ml and nonoxynol-6 5 ml. A synergistic compositionmay be formulated as follows: phenyl 2-acetoxyethanoic acid or diphenyl2-acetoxyethanoic acid 1 g and clotrimazole 1 g were dissolved inethanol 78 ml and propylene glycol 20 ml.

The participating subjects in the present study were instructed to applytwice daily the composition containing phenyl 2-acetoxyethanoic acid ordiphenyl 2-acetoxyethanoic acid with or without clotrimazole as anadditional antimicrobial agent. Nail infections usually disappearedwithin one to several months of topical application with thenon-synergistic composition. The synergistic composition appeared toshorten the period of topical application and speed-up the healing ofdiseased nails.

EXAMPLE 13

Compositions for treatment of oral infections may contain an aryl2-acetoxyethanoic acid as the only active ingredient. In this case aphenyl 2-acetoxyethanoic acid or diphenyl 2-acetoxyethanoic acid 2%composition was formulated by dissolving the active ingredient 2 g inethanol 78 ml and propylene glycol 20 ml. Before use, this compositionwas diluted to 0.1% with water by mixing one part of the compositionwith 19 parts of water. The treatment involves oral rinse, wash andgargle by keeping the diluted composition inside the oral cavity for afew minutes, and then spit out. Such procedure may be repeated twicedaily for several days until the infection is eradicated usually within5-7 days.

A synergistic composition may be formulated by dissolving phenyl2-acetoxyethanoic acid or diphenyl 2-acetoxyethanoic acid 1 g and apharmaceutical agent such as ketoconazole or acyclovir 2 g in ethanol 77ml and propylene glycol 20 ml. Before use, this composition was mixedwith 19 parts of water. Oral treatment was carried out in the sameprocedure as the above.

EXAMPLE 14

Compositions for topical treatment of vulvar-vaginal infections maycontain an aryl 2-acetoxyethanoic acid as the only active ingredient. Inthis case, phenyl 2-acetoxyethanoic acid or diphenyl 2-acetoxyethanoicacid 0.3 g was dissolved in ethanol 1 ml. The solution thus obtained wasmixed with petrolatum 66 g and mineral oil 32.7 g. The ointment thusprepared may be applied topically twice daily to the affected areas fora few days to a few weeks.

A synergistic composition may be formulated by dissolving phenyl2-acetoxyethanoic acid or diphenyl 2-acetoxyethanoic acid 0.1 g andclotrimazole 0.2 g in ethanol 2 ml and nonoxynol-6 5 ml. The mixturethus obtained was mixed with petrolatum 66 g and mineral oil 26.7 g. Thetopical formulation thus prepared may be applied twice daily to theaffected area until the infection has subsided.

EXAMPLE 15

An aryl 2-acetoxyethanoic acid may be incorporated in food products,cosmetic and pharmaceutical formulations and industrial preparations asa preservative to prevent the growth of microorganism(s) . Theconcentration of an aryl 2-acetoxyethanoic acid used may range from0.01% to 1% with a preferred concentration of 0.02% to 0.2%.

An aryl 2-acetoxyethanoic acid may also be used in compositions as aroutine oral hygiene aid. The concentration of the active ingredient mayrange from 0.01% to 0.5% with preferred concentration of 0.02% to 0.1%.An aryl 2-acetoxyethanoic acid may also be incorporated into soaps, soapbars, sticks, balms and the like for personal care and routine hygienecare. The concentrations may range from 0.01% to 1% with preferredconcentration of 0.02% to 0.5%.

Test Results Overview

In order to determine the antimicrobial effect of an aryl2-acetoxyethanoic acid, a standard test method of Minimum InhibitoryConcentration (MIC) against the growth of 10 bacteria was used. Todetermine a prophylactic effect against the development of, as well as atopical effect in the treatment of, body foul door, eleven humansubjects participated in this study. More than twenty human subjectsparticipated in a study to determine whether the compositions containingan aryl 2-acetoxyethanoic acid were therapeutically effective fortopical treatment of folliculitis and other skin lesions, nailinfections and mucosal infections caused by microbial infections.Scientific and test results are overviewed as follows.

I. Antimicrobial Test

Ten different species of bacteria were used in Minimum InhibitoryConcentration (MIC) tests. The bacteria include S. aureus, S.epidermidis, M. sedentarius, M. luteus, B. epidermis, C. minutissium, S.marcescens, P. aeruginosa, E. coli, and P. acnes. In addition varioussources and strains of these bacteria were also included in the tests,and up to 32 different strains of P. acnes were used.

The test substance selected from phenyl 2-acetoxyethanoic acid, benzoylperoxide, chlorhexidine gluconate and triclosan was dissolved in water,and the solution with serial dilution was incorporated into the testagar plates. The plates containing different concentrations of testsubstance were inoculated with a strain of bacterium. MIC is defined asthe lowest concentration of the test substance in the plate in whichthere is no growth of the microorganism.

Phenyl 2-acetoxyethanoic acid showed inhibitory effects against thegrowth of all ten bacteria tested, with or without the presence of 10%lipid materials. The compound of the present invention was specificallyeffective against P. acnes at 0.025% concentration even in the presenceof lipid materials.

In some instances, different strains of one bacterium might have givenrise to slightly different inhibitory effects. In general, however,different sources or strains of the same species were found to givebasically very similar results. For example, five strains of S.epidermis from 5 sources with numbers Atcc 35984, Atcc 31432, Atcc14490, Dh 557 and Dh 640 gave identical results. Thirty-two differentstrains of P. acnes (twenty from acne lesions and the remaining twelvefrom other sources) all gave identical results.

Under the same test conditions, benzoyl peroxide at 0.0625%concentration showed inhibitory effects against M. sedentarius, M.lutens, and P. acnes in the presence of 10%. lipid materials. Thisantiacne compound was not effective against the growth of all thebacteria tested in the absence of lipid materials.

Chlorhexidine gluconate at 0.02 to 0.05% concentration is used as ageneral antiseptic on skin and mucous membranes. Under the same testconditions chlorhexidine gluconate at 0.006 to 0.1% concentration wasfound to be effective against all the bacteria tested in the absence oflipid materials. However, this antiseptic substance was not effectiveagainst the growth of all the bacteria tested in the presence of lipidmaterials.

Triclosan at 1% concentration is used in liquid and bar soap as adisinfectant and medicated cleanser for acne-prone skin. Under the sametest conditions triclosan at 0.0156% concentration was found to beeffective against all the bacteria except S. marcescens and P.aeruginosa in the absence of lipid materials. However, this disinfectantwas not effective against the growth of all the bacteria tested in thepresence of 10% lipid materials.

The above antimicrobial test results show that the phenyl2-acetoxyethanoic acid is the most active and effective compound againstP. acnes with or without the presence of lipid materials in the testmedium.

II. Body Odor

A. Axillary Foul Odor

A total of seven subjects (four females ages 62, 64, 78, and 81; threemales ages 36, 38 and 68) participated in several studies. Most of thesesubjects could not use existing commercial products of antiperspirantsor deodorants because of severe irritation after topical application.Phenyl 2-acetoxyethanoic acid or diphenyl 2-acetoxyethanoic acid 0.5%concentration and a control vehicle (70 volume % ethanol, 30 volume %propylene glycol) were prepared in one-ounce container bottles accordingto the examples. The participating subjects were instructed to take ashower in the morning using ordinary soap to clean the body surfaces.After the skin was dried, the test composition containing 0.5% aryl2-acetoxyethanoic acid was topically applied to the left underarm areaonly. The control vehicle was topically applied to the right underarmarea. Topical applications were repeated 8 hours later.

Both underarm areas were monitored by the subject and at least one otherperson approximately every 8 hours to determine whether the testcomposition had any prophylactic effect in preventing the development ofunderarm foul odor in the left axilla as compared to the vehicle aloneon the right control underarm. The criteria for ineffectiveness oreffectiveness of the test composition were based on presence or absenceof foul odor as detected by olfactory sense of smell. It was found inall the participating subjects that while the right control sidedeveloped underarm foul odor by 8 hours, the left axilla did not produceany detectable odor, even after 16 hours. This test result shows thatthe composition containing 0.5% aryl 2-acetoxyethanoic acid is topicallyeffective in preventing the development of axillary foul odor.

The axillary antiodor effectiveness was determined as follows. The aboveparticipating subjects were instructed to topically apply the testcomposition containing 0.5%; phenyl 2-acetoxyethanoic acid or diphenyl2-acetoxyethanoic acid on the right underarm and discontinue the use ofthe control vehicle after the foul odor had developed. The subjectscontinued to use the same test composition containing 0.5% phenyl2-acetoxyethanoic acid or diphenyl 2-acetoxyethanoic acid on the leftunderarm. Topical applications were repeated 8 hours later. Thereaftertopical applications were made once daily for several days. In all thesubjects tested the right axilla ceased to emanate any detectable foulodor after 2 to 3 days of topical use. The left axilla continued tomaintain the condition free of any offensive foul odor.

In another study the subjects were instructed not to take a shower inthe morning. After the foul odor developed in both axillae, the subjectswere instructed to apply the test composition containing 0.5% phenyl2-acetoxyethanoic acid or diphenyl 2-acetoxyethanoic acid on the leftunderarm area and the control vehicle on the right underarm area.Topical applications were made once daily for several days.

While the right underarm continued to produce foul odor, the leftunderarm diminished in intensity of foul odor after one to two days oftopical application. Usually the left underarm ceased emanating anydetectable foul odor after 1 day of topical use. The subjects wereinstructed at this time to apply the test composition containing 0.5%phenyl 2-acetoxyethanoic acid or diphenyl 2-acetoxyethanoic acid on theright underarm area also. Topical applications were made once daily forseveral days. The right axilla ceased to emanate any detectable foulodor after 1 to 2 days of topical use.

The above results show that the composition containing 0.5% aryl2-acetoxyethanoic acid is topically effective in preventing thedevelopment of axillary offensive odor and is also therapeuticallyeffective for topical treatment of underarm foul odor.

B. Foot Malodor

A total of six subjects (three females ages 23, 35, and 57; three malesages 43, 61 and 70) participated in several studies. Most of theseparticipants had used commercially available products for foot malodorincluding those containing a mixture of undecylenic acid and zinc orcalcium undecylenate without much success in controlling the developmentof foot malodor.

A test composition containing 1% phenyl 2-acetoxyethanoic acid in powderform was prepared by mixing thoroughly 1 g of finely powdered compoundwith 99 g of talc powder. The talc powder alone was used as a controlvehicle. The test composition and the control vehicle were packaged inone-ounce powder containers. The participating subjects were instructedto lightly spread the test composition on the bottom of the left footand inside the hose or sock on the first morning.

The criteria for ineffectiveness or effectiveness of the testcomposition were based on presence or absence of malodor as detected byolfactory sense of smell. Both feet were monitored by the subject and atleast one other person in the evening. While the right foot developedmalodor by the first evening, the left foot produced no detectablemalodor in all the participating subjects.

The subjects were then instructed to apply the test composition on bothfeet the next morning. At the end of the second day, both feet producedno detectable malodor. The same topical applications were continued byall the participants for several days to confirm the above results.

The test results show that the test composition containing 1% phenyl2-acetoxyethanoic acid was topically effective in preventing thedevelopment of and was also therapeutically effective for topicaltreatment of foot malodor.

III. Folliculitis and Perifolliculitis

Nine patients having various degrees of folliculitis andperifolliculitis participated in this study. A test compositioncontaining 0.9% phenyl 2-acetoxyethanoic acid or diphenyl2-acetoxyethanoic acid was prepared by dissolving 0.9 g compound in 79.1ml 2-propanol, 15 ml butane-1,3-diol and 5 ml nonoxynol-6. Thecomposition was packaged in one-ounce bottles. The patients wereinstructed to apply the test composition twice daily on the infectedskin lesions and involved areas. Topical applications were continued upto 8 weeks. The results showed that skin lesions of superficialfolliculitis and perifolliculitis were eradicated or substantiallyimproved after a few days of topical applications. Deeper lesions ofpapules were found to be eradicated or substantially improved after 4 to8 weeks of topical applications.

IV. Therapeutic Response and Amplified Effects

(a) Acne

Twelve patients having moderate to severe acne lesions consisting ofpustules and papules participated in this study. The test compositioncontaining 2% salicylic acid and 1% phenyl 2-acetoxyethanoic acid ordiphenyl 2-acetoxyethanoic acid was prepared by dissolving 2 g salicylicacid and 1 g aryl 2-acetoxyethanoic acid in 70 ml ethanol, 26 mlpropylene glycol and 1 ml nonoxynol-6 or 1 ml nonoxynol-11.

The patients were instructed to topically apply the test compositiontwice daily on the affected areas of the skin for 4 to 8 weeks. Acnelesions were recorded at the beginning and at the end of 4 weeks and 8weeks of topical applications. Ten of twelve patients showed substantialreduction in the number of pustular and papular lesions after 4 to 8weeks of topical treatment with the test composition containing bothsalicylic acid and phenyl or diphenyl 2-acetoxyethanoic acid. Oncontinued use of the test composition new lesions of pustules andpapules did not appear over the next 8 weeks. This indicated that thetest composition has a prophylactic effect in preventing the developmentof new acne lesions.

(b) Psoriasis

Psoriasis is not an infection disease but rather a disorder caused bygenetic factors and is a chronic skin disease affecting approximately 1to 3% of the population. This disease is characterized by silver scalesand thick, dry, red skin. Although corticosteroids such as clobetasolpropionate, betamethasone dipropionate, betamethasone valerate andtriamcinolone acetonide are topically effective in the control ofpsoriatic lesions, many patients have developed resistance to continuedmedications.

To determine the therapeutic responsive effect of an aryl2-acetoxyethanoic acid against psoriasis seven patient participated inthis study. A test composition was prepared by dissolving 1 g phenyl2-acetoxyethanoic acid or diphenyl 2-acetoxyethanoic acid in 2 mlethanol. The solution thus obtained was mixed with 60 g petrolatum and37 g mineral oil. The anhydrous ointment thus formulated was packaged inone-ounce jars.

When the drug unresponsiveness to a corticosteroid occurred, theparticipating patients were instructed to apply in addition the testcomposition once daily to the lesions on the left side of the body only.Topical applications of the corticosteroid were continued twice daily toboth sides of the body. Psoriatic lesions on the left side of the bodybegan to improve after one week of additional topical application withthe composition containing phenyl 2-acetoxyethanoic acid or diphenyl2-acetoxyethanoic acid. While psoriatic lesions on the right side of thebody remained unresponsive to the topical corticosteroid, the lesions onthe left side started to clear after 3 to 4 weeks of additional topicalapplication with the composition containing an aryl 2-acetoxyethanoicacid.

At this time the patients were instructed to shift the additionaltopical application to the lesions on the right side instead of the leftside of the body. The psoriatic lesions on the right side of the bodybegan to clear after 3 to 4 weeks of additional topical application withthe composition containing aryl 2-acetoxyethanoic acid.

We have also found that the test composition containing aryl2-acetoxyethanoic acid could be used in conjunction with acorticosteroid product at the beginning of topical treatment to preventthe development of tachyphylaxis to corticosteroid.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications within the spirit and scope of thepresent invention as defined by the appended claims.

What is claimed is:
 1. A method for treating or preventing the spread ofacne vulgaris, comprising topically applying to an affected area of theskin an amount of an aryl 2-acetoxyethanoic acid, excluding phenyl2-acetoxyethanoic acid, effective to eradicate or prevent the spread ofacne vulgaris.
 2. A method according to claim 1, wherein the aryl2-acetoxyethanoic acid has the chemical structural formula ##STR2##wherein R₁ =an aryl group having 6 to 13 carbon atoms, and R₂ =H or anaryl group having 6 to 13 carbon atoms, said acid includingstereoisomers thereof, and free acids or salt forms thereof with anorganic or inorganic base.
 3. A method according to claim 2, whereinwhen R₁ and/or R₂ is an aryl group, the hydrogen atoms of the group maybe substituted by an entity selected from the group consisting of F, Cl,Br, I, OH, acetoxy, C₁ -C₉ lower alkyl, and C₁ -C₉ lower alkoxy.
 4. Amethod according to claim 2, wherein the aryl 2-acetoxyethanoic acid isselected from the group consisting of diphenyl 2-acetoxyethanoic acidand (4-chlorophenyl) 2-acetoxyethanoic acid, (2-chlorophenyl)2-acetoxyethanoic acid, and (4-chlorophenyl) (2-chlorophenyl)2-acetoxyethanoic acid.
 5. A method according to claim 1, wherein thearyl 2-acetoxyethanoic acid is applied in a form selected from the groupconsisting of solutions, gels, creams, lotions, sprays, sticks, balmsand powders.
 6. A method according to claim 5, wherein the aryl2-acetoxyethanoic acid is applied to the affected area in asubstantially anhydrous solution comprising about 0.05% to about 10% byweight of the aryl 2-acetoxyethanoic acid, about 20% to about 80% byvolume ethanol, and about 5% to about 40% by volume propylene glycol. 7.A method according to claim 5, wherein the aryl 2-acetoxyethanoic acidis applied to the affected area as a powder containing about 0.01% toabout 20% by weight aryl 2-acetoxyethanoic acid.
 8. A method accordingto claim 1, wherein the aryl 2-acetoxyethanoic acid is applied in acomposition which also contains a topical agent as synergist oramplifier for cosmetic or dermatological indications of the affectedarea of the skin to which it is applied.
 9. A method according to claim1, wherein the aryl 2-acetoxyethanoic acid is diphenyl 2-acetoxyethanoicacid.